Phenytoin (Epanutin) Associated Hodgkin's Disease.

We report a case of phenytoin-associated Hodgkin's disease of lymphocyte predominance subtype, which developed after two years of phenytoin (Epanutin) treatment. Four other English cases of phenytoin-associated lmphoid malignancy are also reviewed.


INTRODUCTION
pseudolymphoma syndrome is an unusual side 'ect of phenytoin treatment. This syndrome of lym-Pr'adenopathy, fever, rash, hepatosplenomegaly and ??sinophilia usually resolves when phenytoin is stopped though it may sometimes be fatal (4). On rare Occasions phenytoin has also been associated with odgkjn's disease and with non-Hodgkin lymphoma f The link between phenytoin and malignancy was lrst noted in the United States, from which most of the ^ases have been reported. Similar cases have also been ^Ported from Australia (8-9), Israel (10), Spain (11) and aPan (12). However there have been no previous ret,0rts of phenytoin-associated Hodgkin's disease from g6 United Kingdom. We report such a case seen in ristol, and review four other allied cases. CASE REPORT n November 1977, a 28-year-old male steel worker with a S|*-month history of major epilepsy was treated with Pnenytoin 300 mg per day. Physical examination and all ^"oratory tests were normal before treatment. After 18 ?nths of good control, his fits became more frequent. erum phenytoin concentration was found to be suberapeutic, so the dose was increased to 400 mg per aV-In April 1980 he presented with a three week history swelling on the left side of his neck. Examination , ?wed enlarged lymph nodes along the border of the rt sternomastoid and in the right axilla. There was no , sh, fever, hepatosplenomegaly or eosinophilia. The , blood count, plasma viscosity and standard liver nction tests were normal. Serum phenytoin was in the erapeutic range. A clinical diagnosis of phenytoin Seudolymphoma was made (though subsequently f Und to be incorrect), and carbamazepine substituted 0r Phenytoin. I histology of the excised cervical lymph nodes showed of nodal architecture and its replacement by nodules h'ch contained scattered Reed-Sternberg cells of pop-,0rn or polylobated (13) type in a background of small yrnPhocytes (Figure 1). At staging laparotomy no eviress for correspondence: DrT

DISCUSSION
Hodgkin's disease is a not uncommon malignancy and phenytoin is a widely prescribed drug. Therefore, it is possible that the present case represents a chance association. There are no histological features which are specifically characteristic of phenytoin-associated lymphoid malignancies. Thus a direct relationship between drug and malignancy cannot be proven in the present case, or in those reported previously. However, phenytoin has been associated with a ten-fold increase in the incidence of malignant lymphoma (6), and a case-control study found a four-fold increase in phenytoin-associated malignant lymphoma (7).   Spine/malignant lymphoma Four types of histological lymph node change have been recognised in association with phenytoin (14). The first, reactive hyperplasia, is readily recognised on account of the preservation of nodal architecture, although the follicles may be atrophic. The second type of change is the pseudolymphomatous reaction. This resembles angioimmunoblastic lymphadenopathy, and may cause more diagnostic difficulty in view of the distortion of nodal architecture. Numerous immunoblasts, cells resembling Reed-Sternberg cells, focal necrosis often accompanied by vasculitis (15), and occasionally, conspicuous eosinophilia characterises this lymph node reaction, which regresses after withdrawal of phenytoin. In a third type of reaction, 'Pseudopseudolymphoma', the nodes become smaller after stopping phenytoin, but subsequently enlarge with the development of genuine malignant lymphoma. The fourth nodal pathology associated with phenytoin is malignant lymphoma. Most such cases have been of Hodgkin's disease, usually of mixed cellularity, but non-Hogdkin's lymphomas have also been reported (8).
Our case, which lacked reactive features, was clearly an example of Hodgkin's disease. Unlike the majority of such lymphomas seen in association with phenytoin, it was of the nodular lymphocyte-predominance subtype. It is important to note that features of the phenytoin pseudolymphoma syndrome, such as skin rashes, fever, gum hypertrophy and blood eosinophilia, were absent in the patient reported here and in those with malignant lymphoma reported earlier.
The mechanism by which phenytoin causes lymphoid change and malignancy remains unknown. In animals, phenytoin behaves as a hapten, rather than a mitogen, and apparently renders the membranes of lymphoreticular cells antigenic for autologous T lymphocytes (21). It may also cause a failure of normal lymphoproliferative control mechanisms (21). In man, phenytoin depresses cellular and humoral immunity, though there is wide variation between individuals (22,23).
We should like to stress that true malignancy in association with phenytoin is extremely rare, and restricted to the lymphoreticular system. We should therefore not wish to curtail the clinical use of phenytoin, except perhaps in patients with Hodgkin's disease or other lymphoma who are in remission or undergoing active treatment. A careful drug history, with specific questioning regarding phenytoin, should be sought from patients with lymphoid malignancy, and may yield further examples of the association presented here.